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PHARMACOLOGY

Drugs acting on Respiratory System

TOROKHTIN ALEXANDERprofessor, doctor of medical science

biochemistry, pharmacology and physical treatment methods chair-chief

AGENDA: Drugs acting on Respiratory System

Drug for cough and Bronchial Asthma

Cough is a protective reflex – occur due to stimulation of mechano- and/or chemoreceptors of throat,

respiratory passages or stretch receptors in the lung

сough may be useful or useless

Useless (nonproductive) cough should be suppressed. Useful (productive) cough – serves do drain the

airway, its supрression is not desirable, may even be harmful –

so should be stimulated.

Apart from specific remedies – targeted reason of cough reflex – cough, as a symptom may be treated as

a symptom by nonspecific therapy – acting on concomitant pathologic processes

But cough is not the only one symptom occur during lung an respiratory tract pathology –

ventilation disorders – are signals for reasons searching…

Chronic obstructive pulmonary disease (COPD) an inflammatory disease characterized by progressive

bronchiolar fibrosis and alveolar destruction (emphysema) which can occur in variable proportions

The expiratory airflow limitation does not fluctuate markedly over long periods of time, but there are

exacerbations precipitated and provoked by respiratory infections, and/or pollutants. Loss of bronchiolar

elasticity leads to closure of smaller air tubes during expiration. The airway obstruction is accentuated

during exercise causing shortness of breath.

Pharyngeal demulcens

Lozenges

Cough drops

Tinctures containing syrup, glycerine, liquorice

Drugs acting on Respiratory System are classified as

-analeptics – which stimulate autonomic nerve system (acting on respiratory centre);-antitussive drugs;

-lung air flow improving remedies:--broncholitics (anti-asthmatic drugs);

--agents acting on bronchial drenage function (expectorants);-drugs preventing, treating lung oedema (acute pathology of

lung tissue);-antibacterial (if infection is detected);

-oncologic (anti tumoral).

1.Direct analeptics

bemegrid 0,5%-5ml in isotonic solution of NaCl (acting on respiratory centre of medulla oblongata)

aethimizolum a1-1,5%-5ml (acting on medulla oblongata)coffeinum t0,1; a10%-1ml (acting on cerebral cortex

providing general analeptic effect)

strichnini nitras 0,1%-1ml (acting on medulla spinalis – by stimulating transmission of reflector impulses)

1.2.Indirect (reflectoric) analeptics

-lobelinum hydrochloridum 1%-1ml-citisinum 0,15%-1ml = cititon (Н-cholinergicm, acting in

synocarotid region > activate medulla oblongata > finaly provide analeptic effect);

-solution of ammonium causticum – NH4OH – integrative act on peripheric nerve receptors with final functional activation of respiratory organs function (like reaction of defence).

1.3.mixed action analeptics

solutio camphorae oleosae 20%-1-2mlsolutio sulfocamphocaini 10%-2mlcordiaminum = solution 25% bisaethylamid of nicotinic acid

carbogen= O2 - 93-95%+CO2 - 5-7%

Antitussive (Cough centre supressants)a.Opioids

Codein, Ethylmorphineb.Nonopioids

Noscapine, Dextromethorphan, Chlophedianolc.Antihistamine

Chlorpheniramine, Diphenhydramine, Promethazined.Peripherially acting

Pronoxdiazine

opioid antitussive

codeinum t0,015 {6-methylmorphine} κώδεια, κοδεια – head (Papaverus somnipherus)

codeini sulphas max=0,1 maxD=0,3aethylmorphini hydrochloridum {6-ethylmorphine}max=0,03

maxD=0,1morphini hydrochloridum 1%-1ml

nonopioids narcotic antitussive remedies1Noscapine [narcotine] – an opium alkaloid of

benzoisoquinoline. It depresses cough but has no narcotic, analgetic or dependence inducing properties. Dose: 0,015-0,03

Dextromethorphan – synthetic (central N-methyl D-aspartate receptor antagonist) d-isomer has antitussive action while l-isomer is analgetic. Doea not depress mucociliary function. The antitussive action has been rated equivalent to codein. Dose: 0,01-0,02

Chlophedianol – centrally acting antitussive with slow onset and longer duration. Dose: 0,02-0,04

nonopioids narcotic antitussive remedies2

glaucini hydrochloridum t0,04-0,05]

{alkaloid of – Glaucinum flavum}[glauvent, tussiglaucin] t0,05A componente of various

anti-cough mixtures: “bronchlitin”

Glaucium Flavum Crantz.

synthetic antitussive remedies

libexin t0,1] [prenoxdiazine] (cough reflexogen zone blocker) oxeladini citras t0,01 syrup 1мл=0,01 [tusuprex, paxeladine]butamirate citrate dr0,005 [stoptusin, sinecod, intusin] atussin [dextromethorphan 0,015 + ascorbinic acid)

2.3.combined non nonkpioid antitussive remediesfalimint [dragee]clophedanol

Peripherally acting antitussives

Prenoxdiazine [Prenoxid] – desensitizes the pulmonary strech receptors and reduce tussal impulses originating in the lungs. Indicated in cough of bronchial origin. Dose: 0,1-0,2

Expectorants (Mucokinetics)a.bronchial secretion enhancers

Sodium/Potassium citrateSodium/Potassium hydrocarbonate

Potassium iodideGuaiphenesine (Glyceryl guaiacolate)

Balsame of ToluVasaka

Ammonium chloride b.mucoliticsBromhexineAmbroxol

Acetyl cysteineCarbocisteine

Differently acting drugs (list)Antitussive-expectorant combinations

3.1. remedies acting on sol-stratum of sputum (local rehydratant and secretolotic) as inhalation

iso- and hyper-tonic solution of sodium chloride [NaCl], sodium bicarbonate [NaHCO3], sodium bensoate, amonia chlorid

[NH4Cl]3.2.bronchial gland stimulants (direct acting)

potassium iodidum [KJ], sodium iodidum [NaJ]3.3.Gastropulmonal mucokinetic – vagus reflex activators

3.3.1.emetins (vomitus starting)3.3.2.saponins (radicorum et rhizomata extracts)

3.3.aetheric oils (folia eucalipti, bud трава чебрецю, плоди анісу, листя евкаліпту, бруньки сосни)

3.4.detergents (surface-active remedies: glycerol, propilenglycol)4.4.combined pharmacologic expectorant remedies

Adjuvant to antitussive drugs (indirect action)

bronchodilators (acting through adrenergic receptors)SalbutamolTerbuthalin

bronchodilators (acting through cholinergic receptors) Ipratropium bromide Oxytropium bromideTiotropium bromide

MethylxantinesTheophyllineTheobromine

3.1. Local broncholitics, rehydratantsSodium chloridum [NaCl]

sol. natrii chloridis isotonica/hypertonica

Sodium bicarbonic [NaHCO3] hydrocarbonatenatrii bicarbonatis p0,5

Sodium bensoas [C6H5COONa]natrii bensoas p0,2

Amonii chloridum [NH4Cl]

Bronchial mucousal glands (direct) stimulants

Sodium/Potassium iodidum (KJ) (NaJ) solutio natrii/kalii iodidum 1%-180ml; 0,3-0,5-1,0 ad usum cum lactis vacci

Ammonia chloridum [NH4Cl] s0,5% ad usum internum

Sodium bicarbonatis [NaHCO3]

sodium hydrogencarbonas pulveris 0,25-0,5

3.3.Gastropulmonal mucokinetic – n.vagus reflex activators

–acting through stomach mucous, it leads to bronchial secretion increasing, insreases ciliar apparatus activity of bronchial epithelium

–also acting on autonomic nerve ganglia (chromafin celles of suprarenal glands and on synocarotide reflectoric zone)

3.3.1.emetins (vomitus inducing) indirect actingherba thermopsidis lanceolata [inf-1:300][contains citisin (Mixtura sicca contra tussim pro adult)

infusum ex 0,6 – 180 ml; extractum siccum t0,01]radix ipecacuanae

Indirect acting on respiratory tract through due to chemical compounds

Saponin containig plantsradix althaeae officinalis; inf.1:30 {ex 6,0 – 180 ml} (Mixtura sicca

contra tussim pro infantibus)mucaltinum t0,05 – herba althea (polysaccharides)radix glycyrrhyza (солодка) inf.1:30radix polemonium (синюха) inf.1:30radix inula (оман) inf.1:30radix polygala (істод) inf.1:30 folia tussilago farfara (підбіл звичайний) inf.1:30herbae thymus serpillum (чебрець) inf.1:30herbae viola tricolor (фіалка триколірна) inf.1:30

Aetheric oils

herba Thymi serpilli; [pertusin = 12 чебрецю +1 KBr +82 syrupi sacchari +5spiritus eathylicum]

liquor ammonii anisatus = [olei anisati 2,8m1 sol. Ammonii caustici 15ml, spiritus aethylicus 90% ad 100ml]

folium eucaliptituriones pini (паростки бруньки сосни )terpinum hydratum pt0,25 [para-menthandiol-1,8-hydrate]

Mucoactive remedies

4.1. Mucoactive remedies, acting on synthesis of sputum secretion

4.2. Mucoactive remedies, acting on polymeric bonds of sputum

4.3.detergents (surface tention decreasing agents (secretoroics – decrease adgesive properties of

sputum) (sorbetol, sodium bicarbonic)4.4.bronchial mucousalglands blocking agents

4.5.surfactant acting and related drugs

Cystein derivatescystein

With ammonia blocked group priventes peptid bond condensation which form mucoproteins and mucopolycarbohydrates

acetylcysteinum [ACC, mucosolvin]t0,2-0,4-0,6 a10-20%-2-10ml

Carbocystein (lysinic salt), aethylcystein, methylcystein

acethyl cystein

synthetic mucolitics (tiolitics)

Stepronin

mesna2-MercaptoEthane Sulfonate Na (mistabron)

synthetic mucolitics (tiolitics)

Letostein

mucolytics (direct acting on bronchial secret – solving bronchial secret

[if increased adgesity]) 4.2.1.Proteolitic enzymestrypsinum a0,005chimotrypsinum f0,005ribonucleasum f0,005desoxyribonucleasum (pulmosim) f0,005(lizozym, streptokinaza, α-amilasa) 4.2.2.Drugs acting like hydratants of bronchial secret

(mucohydrants) inorganic compounds of iodine – potassium and sodium [KJ, NaJ], hypertonic salt solutions of NaCl

Detergents

4.3.detergents – decreases surface tension of bronchial secretbronchorhoics – are decrease adgesivity of secret -glycerol-propilenglycol-sodium bicarbonatis pro inhalationes

4.5.acting on surfactant4.5.1.surfactant synthesis stimulators

bromhexynum (bisolvin, solvin, phlegamin) t0,008; a0,004ambroxol (lasolvan, mucobron, ambroxan, ambrobene, ambrohexal) t0,03 a0,75%-2ml [ambroxol-retard t0,075]

4.5.1.surfactant substitutorsalveofact purifide surfactant suspension for intratracheal

instillationexosurf (distress syndrom at newly born child)

sucrim

4.4.drugs acting on bronchial secretion activity. Mucousoactive agents.

4.4.1.alkaloid derivates bromhexin

ambroxol (syrup 0,015/5ml = sol 0,3%)

(ambroxol is a metabolit of bromhexin)

Drugs for bronchial asthmaapproaches to treatment

1.prevention of antigen-antibody reaction (if antigen can be identified)

2.Neutralization of IgE (reaginic antibody)3.Suppression of inflammation and bronchial hyperreactivity

4.Prevention of release of mediators (mast cell stabilizers)5.Anthagonism of released mediators (leucotriene antagonists,

antihystamines platelet activating factor (PAF) antagonists6.Blockade of constrictor neurotransmitter (anticholinergics)

7Mimicking dilator neurotransmitter (sympathomimetics)8Directly acting bronchodilators

Adrenomimetics

5.1.1.α- and β-adrenomimeticsadrenalini hydrochloridum 0,1%-1ml

Indirect acting adrenomimeticsephedrine hydrochloridum 5%-1ml, t0,05

5.1.2. β1+ β2-adrenomimeticsisadrinum t0,001; a1%-25ml

orciprenalini sulfas [alupent, aspopent]

Bronchodilators

β2 SympathomimeticsSalbutamolTerbutalineBambuterolSalmeterolFormoterolEphedrine

β2-agonists5.1.3. β2-adremomimetics (β2-agonists)

-short acting (duration of acting in hours)Phenoterol (4-6) [phenoterolum dose=0,0002] (berotek) Salbutamol (4-6) [salbutamolum] (ventonil, combivent)

Terbutalin (4-6) [terbuthalinum] (bricanil)Levosalbutamol (6-8)

-long acting (duration of acting in hours)Formoterol (12+)

Arformoterol (12+)Indecaterol (24)

Salmaterol (12+) [salmeterol]=serevent [clenbuterol]

Bronchodilators

Methylxantines

Theophylline (anhydrous)Aminophylline

Choline theophyllinateHydroxyethyl theophylline

Theophylline ethanolate of piperazineDoxophylline

Bronchodilators

MethylxantinesTheophylline (1,3 Dimethylxanthine) Theobromine (3,7 Dimethylxanthine) Caffeine (1,3,7 Trimethylxanthine)

source alkaloid content in beverage in an average cup

Thea sinensis Caffeine 0,05 (Tea leaves) Theophylline 0,001

Coffea arabica Caffeine 0,075(coffee seeds)

Theobroma cacao Theobromine 0,2(cocoa, chocolate) Caffeine 0,004

Cola aciminata Caffeine 0,03(Guru nuts) (in 200 ml bottle of cola drink)

Euphylline (solution 2,4% and 24%)

[euphylline is a mixture of theophylline 80% and 1,2 – ethylendiamin 20%]

Anticholinergics

(also blocking tromboxan А2)

atropini sulfas Aer0,0001-0,00025; amp:0,1%-1mlplatiphillini hydrotartras amp:0,2%-1ml

metacinum amp: 0,1%-1ml

Anticholinergics

short actingIpratropium bromide (6-8 hours)

[atrovent aerosol 15ml 1 dose=0,0002]

Oxytropium bromide (6-8 hours)

long actingTiotropium bromide (24+ hours)

Combined Bronchodilators

BERODUALFenoterol + Ipratropium bromid

inhalator (200μg/80μg)nebulizer (1,25μg/0,5μg)

Salbutamol + Ipratropium bromidInhalator (75μg/15μg)

nebulizer (0,75μg/0,5μg)

Corticosteroids

a.SystemicHydrocortizone

Prednisolone

b.InhalationalBeclomethasone dipropionate

BudesonidFluticasone propionate

FlunisolideCiclesonide

Combined bronchodilators

β2-agonists long lasting effect + corticosteroids

Formoterol + Budesonidinhalator(4,5μg/160 μg)

Salmeterol + Flutikasone propionatinhalator(50 μg /100 μg)

Leucotriene antagonists

MontelucastZafirlucast

Mast sell stabilizers

Sodium cromoglycateKetotifen

Inti-IgE antibody

Omalizumab

Choice of treatment (asthma)1.Mild episodic asthma

(symptoms less then one daily, normal in between attacks: inhalation of short acting β2-adrenagonist)

2.Seasonal asthma(low-dose inhalation of steroids 200-400μg/day

cromoglycate 3-4 weeks before anticipated seasonal attacks)

3.Mild chronic (persistent) acthma with occasional exacerbrations

(symptoms one daily, subnormal ventilatory perfomence – regular low-dose inhalation of steroids

100-500μg/day)

4.Moderate asthma with frequent exacerbation(attack more than one daily – inhalation of steroids up

to 800μg/day + long acting β2-adrenagonist)

5.Severe asthma(continuou symptoms, activity limitation, frequent

exacerbation - inhalation of steroids up to 800-2000μg/day + long acting β2-adrenagonist twice

daily)

6.Status asthmaticus/Refractory asthma(hydrocortisone hemisuccinate 100 mg

nebulized salbutamol 2.5-5 mgipratropium bromide 0.5 mg

high flow humidified inhalation of O2salbutamol/terbutalin 0.4 mg i.m./s.c.intubation and mechanical ventillation

correct dehydratationsol.bicarbonat infusion)

Antihistamin acting drugs and

Antibiotics

will be discussed and observed separately

Thank YOU for ATTENTION